Pancreatic ductal adenocarcinoma (PDA) is a deadly human cancer with a overall 5-year survival rate of less than 5%. Better preventive and treatment strategies are desperately needed for this disease. Unlike most other solid malignancies, PDA is surprisingly homogeneous genetically. The great majority (>90%) of human PDA contain a unique genetic signature: they have activating mutations of the Kras proto-oncogene. The critical role of Kras activation in the development of this malignancy is supported by studies showing that mice expressing an activated Kras mutant in pancreatic cells develop the full spectrum of premalignant and malignant tumors commonly found in pancreatic cancer patients. This proposal addresses an important research question with high translational value: does downregulation of phosphatidylinositol 3-kinase (PI3K) p110 prevent the development or block the progression of pancreatic cancer induced by oncogenic Kras? Aim 1 uses molecular and cellular studies to gain mechanistic insight into how PI3K p110 regulates and is regulated by Kras. Results from these experiments will increase our knowledge regarding how to treat all Kras-induced cancers. Aim 2 uses genetic ablation of PI3K p110 in a mouse model of PDA induced by Kras and p53 mutations to test if p110a is a viable therapeutic target in pancreatic cancer. Aim 3 uses a pharmacological approach to investigate if chemical inhibition of PI3K prevents is a safe approach to prevent the development of PDA in the Kras induced tumors. Results from this study have obvious clinical implications for the testing of existing PI3K inhibitors and for the development of novel compounds in this class. Successful completion of our animal studies should lead to investigation of natural and synthetic PI3K inhibitors as a chemopreventive intervention for pancreatic cancer in humans.